1.alpha.,25- Dihydroxycholecalciferol is represented by the formula: ##STR1##
The compound has a molecular weight of 416.647, a molecular formula of C.sub.27 H.sub.44 O.sub.3, is soluble in organic solvents and practically insoluble in water.
The generic name of 1.alpha.,25-dihydroxycholecalciferol is calcitriol.
1.alpha.,25-Dihydroxycholecalciferol stimulates intestinal calcium and phosphorus absorption and, with parathyroid hormone, stimulates bone calcium resorption or mobilization. 1.alpha.,25-Dihydroxycholecalciferol meets the criteria of a classic steroid hormone in that it is synthesized in one organ under closely regulated conditions, and is then transported by the circulation to another organ where it exerts its biological effects.
The discovery that the kidney is the exclusive site for the production of 1.alpha.,25-dihydroxycholecalciferol from 25-hydroxycholecalciferol provided an explanation for the vitamin D-resistant state observed in patients with chronic uremia. Blood levels of 1.alpha.,25-dihydroxycholecalciferol in patients with chronic renal failure are low or undetectable. The successful chemical synthesis of 1.alpha.,25-dihydroxycholecalciferol made this metabolite available for replacement therapy, and its clinical use for the treatment of hypocalcemia in patients on renal dialysis has recently been approved.
The effectiveness of this drug in several other clinical conditions has been reported in the scientific literature. These investigational uses of 1.alpha.,25-dihydroxycholecalciferol include the treatment of renal osteodystrophy, hypoparathyroidism, osteomalacia, osteoporosis, hepatic osteodystrophy, vitamin D-resistant rickets, vitamin D-dependent rickets, childhood renal failure and neonatal hypocalcemia.
Neonatal hypocalcemia is the most prevalent hypocalcemic state encountered in pediatrics and can be divided into two main groups: (1) "early" neonatal hypocalcemia beginning in the first 48 hours of life and (2) "late" neonatal hypocalcemia beginning at the end of the first week of life.
Nearly all infants experience a normal fall in serum calcium during the first few days of life. Early neonatal hypocalcemia appears to be an accentuation of this normal fall in serum calcium, and is often defined as a serum calcium .ltoreq.7 mg/dl or .ltoreq.8 mg/dl for full term infant or a serum ionized calcium level of from about 3 to 3.5 mg/dl. Minimal serum calcium values are reached at 24-48 hours of age with a gradual return to normal in the next few days. Early neonatal hypocalcemia is frequently accompanied by hyperphosphatemia. In unusual circumstances, early neonatal hypocalcemia may persist for a week or more, and this condition has been called transient congenital idiopathic hypoparathyroidism. Approximately one-third of premature infants (.ltoreq.7 weeks gestation), one-third of infants with birth asphyxia (1 minute apgar score of .ltoreq.6) and one-half of infants of insulin-dependent diabetic mothers have nearly neonatal hypocalcemia.
Low serum ionized calcium level is associated with serious signs including seizures, apnea, vomiting, neuromuscular irritability, gastric atony, cyanosis and lethargy. Hypocalcemia can also occur without signs of neuromuscular hyperirritability. Correlation of clinical signs with serum calcium levels has been difficult because of the many clinical variables coexistant with hypocalcemia in these high risk infants.
Late neonatal hypocalcemia usually occurs in full term or premature infants who have been started on feedings and who show signs or symptoms of hypocalcemia only after several days or weeks of feedings. The hypocalcemia appears to be precipitated by the high phosphate load of most feedings other than human milk. The high phosphate serum concentration in serum of infants in the first few weeks is associated with low parathyroid hormone levels and with a low glomerular filtration rate.
Clinical manifestations of late neonatal hypocalcemia are similar to those described above in connection with early neonatal hypocalcemia. An electrocardiographic sign, prolonged QT interval, can also be present.
1.alpha.,25-Dihydroxycholecalciferol has been shown to be effective in the prophylaxis of neonatal hypocalcemia, however, the preparation of formulations suitable for parenteral administration to neonates has posed a problem due to the irritating nature of the oil-based vehicles used to date for such preparations. In the case of formulations suitable for neonatal administration, it is highly desirable to provide an aqueous parenteral formulation. Prior to the present invention, attempts to provide dilute, aqueous, oil-free solutions of 1.alpha.,25-dihydroxycholecalciferol suitable for administration to infants have failed because of the extreme sensitivity of the material to oxidation, and hence its instability in aqueous solutions. In the case of dilute solutions, if even a small percentage of drug oxidizes, it is impossible to obtain a stable solution.
Thus, there has been a long-standing need to provide an oil-free, stable, dilute aqueous solution of 1.alpha.,25-dihydroxycholecalciferol suitable for oral or parenteral administration to neonates. The present invention fulfills that need and eliminates the need of employing oil base formulations. U.S. Pat. Nos. 3,384,545; 3,070,499; 3,089,922 and British Pat. No. 905,016 describe vitamin D formulations but those formulations are not suitable for 1.alpha.,25-dihydroxycholecalciferol because of this compound's extreme lability to oxygen in dilute aqueous solution.